Mammalian cells have a complex response to DNA damage, as well as a tightly regulated program of replicative senescence, all suggested to be fundamental defenses against cancer [Campisi, J. (1996). Cell 84, 497–500]. In mammals, cell senescence is precipitated by critical shortening of telomeres, tandem repeats of the DNA sequence TTAGGG that cap the ends of chromosomes [Greider, C. W. (1996) Annu Rev Biochem 65, 337–365] and become shorter with each round of DNA replication. In germline cells and most cancer cells, immortality is associated with maintenance of telomere length by telomerase, an enzyme complex that adds TTAGGG repeats dues to the 3′ terminus at the chromosome ends [Feng, J., et al. Science 269, 1236–1241; Harrington, L., et al., (1997) Science 275, 973–977; Nakamura, T. M., et al., (1997) Science 277, 955–957]. The catalytic subunit of telomerase is generally not expressed in normal somatic cells [Greider, C. W. (1996) Annu Rev Biochem 65, 337–365], and after multiple rounds of cell division critically shortened telomeres trigger either replicative senescence or death by apoptosis, largely dependent on cell type [de Lange, T. (1998) Science 279, 334–335], although the detailed mechanism is unknown. The mechanism by which telomeres participate in DNA damage responses has been less clear.
The frequency of cancer in humans has increased in the developed world as the population has aged. Melanoma and other skin cancers have increased greatly among aging populations with significant accumulated exposure to sunlight. For some types of cancers and stages of disease at diagnosis, morbidity and mortality rates have not improved significantly in recent years in spite of extensive research. Cancers are currently often treated with highly toxic therapies. Alternative therapies are needed that could take advantage of the natural mechanisms of the cells to repair environmental damage.